Huntington's disease (HD) is an hereditary neurodegenerative disorder which involves symptoms of dementia and dyskinesia. Neuropathologic studies of HD demonstrate a marked loss of striatal and cholinergic and GABAergic neurons with sparing of the nigro-striatal dopaminergic pathway. We have developed a rat model for HD in which the selective degeneration of striatal intrinsic neurons is caused by direct injection of the conformationally restricted analogue of glutamate, kainic acid. The striatal kainate lesion produced neurochemical and histologic alterations in the nigro-striatal circuit that closely mimic those occurring in HD. Current studies involve a better characterization of the mechanism whereby kainic acid selectively kills striatal neurons since an understanding of this process may shed light on basic pathophysiologic processes involved in the selective and progressive degeneration of neurons in HD. A fundamental approach to be utilized will be the ligand-receptor binding technique. The specific, high affinity binding of (3H)kainic acid to receptor recognition sites in brain will be characterized. Similarly, the specific binding of (3H)L-glutamic acid to putative excitatory recognition sites will also be defined. Possible synergistic interactions between kainic acid and glutamic acid will be explored by kinetic techniques. The ability of drugs and other substances to compete with the recognition site for (3H) kainic acid and to alter its neurotoxicity in vivo will explored. We will attempt to alter the neurotoxicity of kainic acid in vivo through interfering with glutamatergic neurotransmission by pharmacologic techniques. It is conceivable that the mechanisms of neurotoxicity of kainic acid may shed light on the defect responsible for neuronal degeneration in HD.